Dendritic cells (DC) and monocytes/macrophages (Mo/M) are innate immune cells that play a critical role in the host response to viral infection b mediating antiviral activity and inducing adaptive immune responses. However, in human immunodeficiency virus (HIV) infection of humans this relationship between DC, Mo/M and virus control is not clear, as generalized immune activation that is a central feature of progression to AIDS may be driven by an overactive innate immune response to infection. Hence, a central unanswered question in HIV pathogenesis is whether the DC and Mo/M response to infection is desirable or detrimental. This represents a critical impediment to progress in the field, as we do not know if therapeutic strategies should be aimed at blocking or promoting innate immunity. In this proposal we will address this central question in simian immunodeficiency virus (SIV) infection of rhesus macaques, which models HIV infection of humans. We will prospectively study the DC and Mo/M response in SIVmac251-infected macaques with controlled infection vs. normal or rapid progression and compare this to macaques infected with SIVmac251 and treated with antiretroviral therapy or infected with attenuated SIVmac239nef. With this full spectrum of outcomes of infection we will be able to put into context the relevance of the DC and Mo/M response to AIDS pathogenesis. In addition, we will use a novel humanized antibody specific for one subset of DC, the plasmacytoid DC, to deplete these cells at the time of infection or during the chronic phase. This will, for the first time, allow us to directly determine the contribution of plasmacytoid DC to virs control and chronic immune activation. These hypothesis-driven studies will further define the role of DC and Mo/M in HIV infection and provide direction for development of therapeutics targeting innate immunity.